Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → tert-Butyl 1-[3-({(3R)-N-[(allyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-chlorobenzyl]cyclopropanecarboxylate

HRID 626429Notes

Reaction equation

HRID 626429 reaction equation
[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:15]([OH:17])=O)[C@H:9]([C:11]([F:14])([F:13])[F:12])[CH3:10])=[O:6])[CH:2]=[CH2:3].[NH2:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:22][C:23]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:15]([NH:18][C:19]1[CH:20]=[C:21]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:22][C:23]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]1)=[O:17])[C@H:9]([C:11]([F:12])([F:13])[F:14])[CH3:10])=[O:6])[CH:2]=[CH2:3]

Participants

6

Reactant 3

HCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 67957815tert-Butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate2×HCID 118106697(3R)-N-[(Allyloxy)carbonyl]-4,4,4-trifluorovaline

Product 1

HCID 118106369tert-Butyl 1-[3-({(3R)-N-[(allyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-chlorobenzyl]cyclopropanecarboxylate

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6228DimethylformamideSolvent

Procedure

398.5 mg (1.56 mmol) of (3R)—N-[(allyloxy)carbonyl]-4,4,4-trifluorovaline (diastereomer mixture) and 400 mg (1.42 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate were dissolved in a mixture of 4.7 ml of DMF and 1.6 ml of pyridine, and 647.8 mg (1.70 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight. A further 400 mg (1.42 mmol) of tert-butyl 1-(3-amino-4-chlorobenzyl)cyclopropanecarboxylate and 647.8 mg (1.70 mmol) of HATU were added, and the reaction mixture was stirred at 50° C. for another 4 h. After dilution with ethyl acetate, the mixture was washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water). This gave 453 mg of the target product (55.9% of theory, diastereomer ratio >8:1).

Workup

  1. additionwere added at RT
  2. stirringthe reaction mixture was stirred at 50° C. for another 4 h
  3. washAfter dilution with ethyl acetate, the mixture was washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution
  4. dry with materialdried over magnesium sulphate
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was purified by preparative RP-HPLC (mobile phase: acetonitrile/water)

Sources & evidence

ORD record
ord-fe71ebb17eea48cc810535b6aa684340
Source dataset
uspto-grants-2016_04
Patent number
US09309198B2

Reaction notes

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